Solid mammary tumors are induced in nude mice by s.c. injections of the human breast cancer cell lines MCF-7 or ZR-75. Tumor induction and metastases to lungs, liver and spleen by MCF-7 cells are insulin-dependent and estrogen-dependent. Prevention of metastases and tumor regression can be obtained by the simultaneous estrogen withdrawal (ovariectomy) and treatment with the antiestrogen tamoxifen. Effective tumor regression can also be obtained with the simultaneous estrogen deprivation and insulin withdrawal (induction of diabetes with streptozotocin). MCF-7 cells secrete into the culture media plasminogen activator and collagenases able to lyse type I and IV collagens. These enzymes are under positive regulation by insulin and estrogen. We are investigating the in vitro - in vivo relationship between these biochemical effects of the hormones and their control over mammary tumor growth. We have also designed experiments on combined endocrine and chemotherapeutic protocols that lead to effective tumor regression.